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ID PMID Title PublicationDate abstract
10379464 Defining patients at risk of non-steroidal anti-inflammatory drug gastropathy. 1999 Non-steroidal anti-inflammatory drugs have long been known to cause gastro-duodenal damage. However, all parts of the gastrointestinal tract may be affected, including the small intestine, colon and oesophagus. Non-steroidal anti-inflammatory drugs can cause dyspeptic symptoms, erosions, ulceration, which may lead to haemorrhage or perforation, and a requirement for surgery. The purpose of this report is to assess risk factors which may lead to gastrointestinal damage and, thus, to identify those patients at greatest risk of non-steroidal anti-inflammatory drug damage. Possible risk factors include age, sex, previous ulcer history, the presence of Helicobacter pylori, the type and severity of arthritis, individual non-steroidal anti-inflammatory drugs (dose, duration of treatment, route of administration), other debilitating diseases, smoking, alcohol, and the use of concomitant drugs. Risk of non-steroidal anti-inflammatory drug damage is higher in older patients (RR > 60 5.52; < 60 1.65), but there is no convincing sex difference. There is increased risk in patients with a previous history of peptic ulceration (RR first gastrointestinal event 2.39; subsequent gastrointestinal event 4.76), and in the first three months of treatment. Debate continues about the relevance of Helicobacter pylori, and this will be discussed in a later report. There is no strong evidence that patients with rheumatoid arthritis are more likely to have more trouble than those with osteoarthritis, but the former are more likely to require higher doses of non-steroidal anti-inflammatory drugs. Highest risk non-steroidal anti-inflammatory drugs include azapropazone, ketoprofen and piroxicam, and those with least risk include ibuprofen, diclofenac and etodolac. There is an increased risk of gastrointestinal complications with relatively small-dose prophylactic aspirin. Other factors increasing the risk are smoking and the presence of chronic underlying respiratory and cardiovascular disease. Risk of gastrointestinal problems is increased with concomitant drugs, especially corticosteroids (RR 14.6 if given with non-steroidal anti-inflammatory drugs), but also with anticoagulants and some other drugs. The clinical importance of identifying possible risk factors lies in being aware of likely problem patients and in the use of safer non-steroidal anti-inflammatory drugs or combination therapy with protective drugs in these patients.
11762939 Activation of the inducible nitric oxide synthase pathway contributes to inflammation-indu 2001 Dec OBJECTIVE: Osteoporosis is a major clinical problem in chronic inflammatory diseases such as rheumatoid arthritis. The mechanism of bone loss in this condition remains unclear, but previous studies have indicated that depressed bone formation plays a causal role. Since cytokine-induced nitric oxide (NO) production has been shown to inhibit osteoblast growth and differentiation in vitro, this study was undertaken to investigate the role of the inducible NO synthase (iNOS) pathway in the pathogenesis of inflammation-mediated osteoporosis (IMO) by studying mice with targeted inactivation of the iNOS gene (iNOS knockout [iNOS KO] mice). METHODS: IMO was induced in wild-type (WT) and iNOS KO mice by subcutaneous injections of magnesium silicate. The skeletal response was assessed at the tibial metaphysis by measurements of bone mineral density (BMD), using peripheral quantitative computed tomography, by bone histomorphometry, and by measurements of bone cell apoptosis. RESULTS: NO production increased 2.5-fold (P < 0.005) in WT mice with IMO, but did not change significantly in iNOS KO mice. Total BMD values decreased by a mean +/- SEM of 14.4+/-2.0% in WT mice with IMO, compared with a decrease of 8.6+/-1.2% in iNOS KO mice with IMO (P < 0.01). Histomorphometric analysis confirmed that trabecular bone volume was lower in WT mice with IMO compared with iNOS KO mice with IMO (16.2+/-1.5% versus 23.4+/-2.6%; P < 0.05) and showed that IMO was associated with reduced bone formation and a 320% increase in osteoblast apoptosis (P < 0.005) in WT mice. In contrast, iNOS KO mice with IMO showed less inhibition of bone formation than WT mice and showed no significant increase in osteoblast apoptosis. CONCLUSION: Inducible NOS-mediated osteoblast apoptosis and depressed bone formation play important roles in the pathogenesis of IMO.
11480483 Women's health after plastic surgery. 2001 Mar BACKGROUND: Allegations that exposure to endogenous silicone, especially related to breast implants, might be causally related to connective tissue disease originated from case studies. More recent comparative studies have implied no such increased risk. The aims of the present study were to compare the prevalence and/or incidence of autoimmune and connective tissue disorders in a population-based cohort of female Sydney residents stratified by augmentation mammoplasty status. METHODS: In this population-based retrospective cohort study, the health status of female Sydney residents who had augmentation mammoplasty for cosmetic reasons between 1979 and 1983 was compared with that of female Sydney residents who had non-silicone-associated plastic surgery over the same period. Both groups were matched for age (+/- 5 years), year of plastic surgery (+/- 2 years), plastic surgeon, anaesthetist and mode of anaesthesia. Outcome measures comprised rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, sicca symptoms polymyositis/ dermatomyositis, connective tissue disease overlap, digital vasospasm, abnormal nailfold capillaroscopy, elevated antinuclear antibody titre, carpal tunnel syndrome, tendonitis, osteoarthritis, psoriatic arthritis, livedo reticularis, thyroid disease, multiple sclerosis, axillary lymphadenopathy, fibromyalgia and breast carcinoma. RESULTS: There was no difference in the occurrence of connective tissue diseases or connective tissue disease-related parameters, thyroid disorders, fibromyalgia or multiple sclerosis between cohorts. However, axillary adenopathy and low titre positive antinuclear antibody (ANA) occurred with a significantly greater frequency in the exposed cohort (odds ratio (OR) = 3.50, 95% confidence interval (CI) = 2.10-5.84 and OR = 1.29, 95% CI = 1.03-1.62, respectively). Axillary adenopathy correlated with capsular contracture (relative risk (RR) = 2.07, 95% CI = 1.22-3.51) and also the self-reported development of digital vasospasm (RR = 3.20, 95% CI = 1.46-7.03) after breast augmentation. CONCLUSIONS: No association was found between augmentation mammoplasty exposure and various connective tissue diseases and/or their related features. However, axillary adenopathy and low titre ANA were detected more frequently in the exposed cohort. Women with axillary adenopathy were more likely to have breast capsular contracture and report digital vasospasm post-dating surgery. Given comparable frequencies of higher titre ANA of both cohorts, the finding of elevations of low titre ANA is of dubious clinical significance.
10972909 Evaluation of diagnostic tests for antinuclear antibodies in rheumatological practice. 2000 Sep To investigate and compare the accuracy and usefulness of diagnostic tests for antinuclear antibodies (ANA) a cross-sectional study of sera derived from patients admitted to the Department of Rheumatology was tested for the presence of ANA using either indirect immunofluorescence on HEp-2 cells, indirect immunoperoxidase techniques on HEp-2 cells and mouse kidney, or two commercial enzyme-linked immunosorbent assays (ELISA). The diagnostic sensitivity and predictive values of the tests were calculated and compared. The accuracy of tests was compared using receiver-operating characteristics (ROC) methodology. All ANA-positive sera were further analysed for the presence of antibodies against extractable nuclear antigens (anti-ENA) and anti-DNA. A moderate to good agreement was found between tests, with kappa ranging from 0.469 to 0.659. Highest sensitivity for systemic lupus erythematosus (SLE; 93.3%) and primary Sjögren's syndrome (SS; 70%) was found using immunofluorescence on HEp-2 cells. Immunofluorescence on HEp-2 cells performed statistically better than the other tests in predicting SLE but not SS. All tests except mouse kidney showed good and comparable performance in detecting sera with anti-ENA and anti-DNA. At the given cut-off values indirect immunofluorescence on HEp-2 cells performed best. All assays except mouse kidney showed performance characteristics sufficient for use in routine analysis of ANA.
10895367 Interferon gamma and tumor necrosis factor alpha induce Fas expression and anti-Fas mediat 2000 May BACKGROUND: We previously reported that Fas antigen was strongly expressed on salivary duct epithelial cells and that some salivary infiltrating cells showed the Fas ligand in patients with severe sialoadenitis due to Sjögren's syndrome (SS). Apoptotic changes were observed in ductal epithelial cells and some infiltrating cells by DNA nick end labeling methods. These findings suggest that the Fas-Fas ligand system may play a role in the pathogenesis of sialoadenitis in SS. OBJECTIVE: To elucidate the mechanism of the de novo expression of ductal Fas antigen in sialoadenitis associated with SS, we investigated the induction of Fas antigen and apoptosis by cytokines in a human salivary duct cell line. METHODS: Human salivary duct cell line (HSG) was cultured with interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), interleukin 2 (IL-2), interleukin 4 (IL-4), and granulocyte monocyte colony stimulating factor (GM-CSF). The expression of Fas antigen in HSG was examined by immunoperoxidase cell ELISA. The appearance of DNA strand breaks during apoptosis induced by anti-Fas antibody was detected by DNA nick end labeling methods. RESULTS: Unstimulated HSG cells constitutively expressed low levels of Fas antigen. IFN-gamma and TNF-alpha consistently upregulated constitutive levels of Fas. In contrast, IL-1 beta, IL-2, IL-4, and GM-CSF had no effect on Fas levels. HSG cells expressing Fas antigen in response to IFN-gamma or TNF-alpha were susceptible to apoptosis by anti-Fas antibody. CONCLUSION: Our findings suggest that IFN-gamma or TNF-alpha secreted by infiltrating lymphocytes induces ductal Fas expression and ductal apoptosis in sialoadenitis associated with SS.
10564552 Light chain variable (VL) sequences of rheumatoid factors (RF) in patients with primary Sj 1999 Nov We have characterized and sequenced the variable (V) region genes of the light (L) chains of 10 immunoglobulin (IgM) rheumatoid factor (RF) monoclonal antibodies (MoAb) derived by the hybridoma/Epstein-Barr virus (EBV) technique from the peripheral blood of patients with primary Sjögren's syndrome (pSS). Six out of 10 RFs used lambda (lambda) L chains, while four RFs used kappa (kappa) L chains. Five out of the six lambda RFs were encoded by Vlambda3 gene segments, the sixth one was encoded by a Vlambda1 gene segment. This preferential utilization of the Vlambda3 family genes suggests selective expansion of the B cell in pSS. Three of the kappa RFs used Vkappa3 gene segments, while the fourth used a Vkappa2 gene segment. Half of the RFs were found as unmutated copies of their closest germline (GL) gene. Interestingly these RFs were previously shown to use heavy (H) chains in GL gene configuration. Three RFs have very few mutations (2-3) and only two RFs have substantial numbers of mutations (6 and 11). This also correlated with the number of mutations in the respective H chains. In contrast to RFs in normal and RA these results further suggest the somatic mutation to be of moderate importance in the generation of RF from the peripheral blood of pSS patients.
10534575 Single cell analysis of T cells infiltrating labial salivary glands from patients with Sjà 1999 Nov Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration into the lacrimal and salivary glands leading to symptomatic dry eyes and mouth. To analyze the function of T cells infiltrating the labial salivary glands, we analyzed T cell receptor (TCR) beta and alpha chains, the expression of various cytokine mRNAs, and apoptosis associated genes in predominant TCR BV2+ T cells in the labial salivary glands of patients with SS at the single cell level. TCR BV2+ T cells in the labial salivary glands were sorted as single cells by flow-cytometry, and then examined by a single cell polymerase chain reaction (PCR). We isolated 18 TCR BV2+ T cell clones from three patients with SS. In six clones, there were highly conserved amino acid motifs (RDxG, GNT, QGxxQETQ) in the CDR3 region of the TCR beta chain. Three of the six clones showed conserved amino acids (EDxTG, or ExxTG) in the CDR3 region of the TCR alpha chain, suggesting restricted T cell epitopes. All TCR BV2+ clones expressed IL-2 mRNA, and six clones were able to produce IL-4, indicating that the cells were Th0 type T cells. All TCR BV2+ clones in the labial salivary glands were CD4+ T cells, and ten clones overexpressed Fas antigen at the mRNA level. In contrast, only one clone expressed Fas-ligand (Fas-L) mRNA, and neither perforin nor granzyme A/B was expressed. In conclusion, these findings support the notion that TCR BV2+ T cells that infiltrate labial salivary glands recognize restricted epitopes and function as CD4+ Th0 type T cells in the induction phase of autoimmunity.
10025917 Analysis of V(H)-D-J(H) gene transcripts in B cells infiltrating the salivary glands and l 1999 Feb OBJECTIVE: In patients with Sjögren's syndrome (SS), B lymphocytes have been found to infiltrate salivary glands, resulting in sialadenitis and keratoconjunctivitis. The disease is frequently associated with benign and neoplastic lymphoproliferation. The present study was undertaken to investigate whether clonal B cell expansion takes place in lymphocytic infiltrations of salivary glands under (auto- [?]) antigen stimulation, by analyzing in more detail the variable part (V(H)-D-J(H)) of the immunoglobulin heavy chain genes expressed in these B cells. METHODS: Biopsies of the labial salivary glands and lymph nodes were performed on 2 female patients with SS. The Ig gene rearrangements in these tissues were amplified by reverse transcriptase-polymerase chain reaction using specific primers. RESULTS: A total of 94 V(H)-D-J(H) transcripts were cloned and sequenced. Our data suggest a polyclonal origin of the B cell infiltrates. In 92 of the transcripts, V(H) genes were modified by somatic mutation. Further analysis showed counterselection for replacement mutations within the framework regions, suggesting that those B cells were stimulated and selected for functional expression of a surface Ig. In labial salivary glands from both patients, clonally related B cells became evident. Members of 1 particular clone were found in both the lip and lymph node material. CONCLUSION: These data provide evidence, on the nucleotide sequence level, that an antigen-triggered clonal B cell expansion takes place in the salivary glands of patients with SS who do not have histologic evidence of developing lymphoma. It may be speculated that those B cell clones expand during disease progression, resulting in lymphomagenesis.
9046736 Lichen planus and Sjögren-type sicca syndrome in a patient with chronic hepatitis C. 1997 Jan We report a 54-year-old Japanese male with lichen planus and Sjögren-type sicca syndrome, accompanied by the latent complication of chronic hepatitis C. The patient first showed erythematous and erosive lesions with white irregular striae in the buccal mucous membrane, and blepharitis and hyperemia of conjunctiva in his eyes. He later had two small erosions on the glans penis, and flat-topped violaceous papules on the dorsa manus and nape. A biopsy specimen of the lower lip lesion demonstrated a lichenoid tissue reaction at the basement membrane zone, and lymphocytic focal accumulations in the salivary glands. Immunohistochemical study of this specimen revealed CD45RO- (T) cells associated with the expression of HLA-DR antigens predominantly in both the lichenoid tissue reaction and the lymphocytic sialadenitis. Objective keratoconjunctivitis sicca was confirmed by the Schirmer and Rose-Bengal tests. Anti-DNA antibody was positive; however anti-SS-A, and anti-SS-B antibodies were negative. Increased levels of transaminase enzymes, TTT, ZTT, and IgG were observed in first laboratory examinations; thereafter, antihepatitis C virus (HCV) antibodies and HCV-RNA were detected. The high serum amylase level, in which salivary amylase predominated, was normalized by etretinate therapy in parallel with the clinical improvement of the oral LP lesions. Our case is considered to support the hypothesis that an etiologic association may be present among lichen planus, Sjögren's syndrome, and chronic hepatitis C.
9023556 Chronic lymphocytic sialoadenitis in HCV-related chronic liver disease: comparison of Sjö 1997 Jan With the aim of morphologically characterizing chronic sialoadenitis in patients with hepatitis C virus (HCV) chronic liver disease, labial salivary gland biopsies from 22 chronic HCV liver disease and from 10 primary Sjögren's syndrome patients were compared. Only focus score (number of aggregates with more than 50 lymphocytes per 4 mm2 of glandular tissue) and grading of inflammation were able to discriminate significantly between the two patient groups. Duct ectasia, acinar depletion, presence of lymphoid aggregates with less than 50 lymphocytes and of lymphoid infiltration within intralobular salivary duct epithelium were evident in both disease groups and appeared to be non-specific, mostly age-related changes. In both patient groups plasma cell and lymphocyte typing showed similar features: T-lymphocytes represented most of the lymphoid population, B lymphocytes were few unless follicles were present. Higher focus score values were associated with a plasma cell switch from an IgA to an IgM and/or IgG predominance. A greater morphological similarity was seen between biopsies of the primary Sjögren's syndrome group and those of female rather than male chronic HCV liver disease patients. Salivary gland tissue in HCV patients responds to damage in a fashion similar to primary Sjögren's syndrome, the only difference being a lesser degree of inflammation.
10921490 Gallium-67 scintigraphic findings in a patient with breast lymphoma complicated with Sjög 2000 Jun We report here a patient with mucosa associated lymphoid tissue (MALT)-lymphoma of the breast complicated with Sjögren syndrome. It is speculated that Ga-67 could accumulate not only in lymphoma lesions but also in benign lymphoproliferative locations of Sjögren syndrome. Gallium-67 scintigraphy might be useful for the diagnosis and therapeutic monitoring of MALT-lymphoma complicated with Sjögren syndrome.
10209623 Bilateral and multicystic major salivary gland disease: a rare presentation of primary Sjà 1998 Dec We present a case of a 15-year-old girl with bilateral parotid and sub-mandibular salivary gland enlargement as the sole presentation of primary Sjögren's syndrome. The clinical, radiological, immunological and pathological features have been discussed. The relevant literature has been reviewed. To our knowledge this is the only reported case of Sjögren's syndrome presenting as multicystic disease with bilateral major salivary gland involvement.
10080830 Activation of nitric oxide signaling through muscarinic receptors in submandibular glands 1999 Feb Primary Sjögren Syndrome is a chronic autoimmune disease characterized by exocrine gland dysfunction. Here we present evidence of the activation of nitric oxide signaling cascade by circulating antibodies of patients with Sjögren Syndrome in rat submandibular glands. Constitutive nitric oxide synthase and cyclic GMP levels are modulated by Sjögren IgGs through the activation of muscarinic acetylcholine receptors on the glands. The effects are similar to those produced by the agonist carbachol and blocked by the antagonist atropine. The involvement of M1 subtype of muscarinic receptors is proposed since both a synthetic peptide homologous to an extracellular domain of M1 receptor and pirenzepine, a selective M1 antagonist, partially blocked the effects. We conclude that Sjögren Syndrome antibodies can activate nitric oxide signaling in submandibular glands by interacting with muscarinic acetylcholine receptors.
9818834 Submandibular and lacrimal gland immunoglobulin in the C3H.MRL-Faslpr autoimmune mouse mod 1998 Nov OBJECTIVE: To distinguish potential autoimmune and nonautoimmune mechanisms underlying the salivary gland inflammation seen in Sjögren's syndrome and normal aging. STUDY DESIGN: Immunohistochemical studies were conducted on the lacrimal and salivary glands of 2- and 5-month-old C3H.MRL-Faslpr autoimmune strain mice and age-matched C3H/HeJ nonautoimmune controls. METHODS: Glandular inflammatory foci, interstitial areas, and vasculature were stained for immunoglobulin G (IgG), immunoglobulin A (IgA), and complement to determine differences in their local immune parameter. Differences between the two strains were compared for immune changes attributable to autoimmune disease and between the two normal groups for normal aging changes. RESULTS: Greater staining of IgG, IgA, and complement occurred in the inflammatory foci and interstitial areas of 5-month-old C3H.MRL-Faslpr lacrimal and submandibular glands compared with 5-month-old controls. Normal mice showed some increased immunoglobulin staining with aging, but little or no complement in any glands. CONCLUSIONS: These differential findings suggest that the systemic autoimmune disease plays a more direct role in focal glandular inflammation in Sjögren's syndrome, whereas less severe immune mechanisms are involved in the inflammation of normal glands.
11778660 Preliminary classification of nonmalignant B cell proliferation in Sjögren's syndrome: pe 2001 Jul A classification of nonmalignant lymphoproliferation in Sjögren's syndrome is presented, based on the results of international meetings regarding Sjögren's syndrome-associated lymphomagenesis and on our results of a clinico-pathologic and molecular study and long-term follow-up in well-characterized patients. Sjögren's syndrome pathobiology has similarities to hepatitis C virus-related B-cell lymphoproliferation. Antigen stimulation with the preferential expansion of rheumatoid factor-positive clones and specific immunoglobulin gene expression and recombination represent key biologic events in lymphoproliferation. This classification is based on the coupling of molecular and histological studies and may result in more selective treatment approaches.
11716205 Inflammation and structural changes in the airways of patients with primary Sjögren's syn 2001 Nov The present study aimed to compare the cellular pattern and structural changes in the airways of patients with primary Sjögren's syndrome (pSS) with healthy controls. Bronchial biopsy specimens were obtained from seven subjects with pSS and seven healthy controls. All the patients with pSS had increased bronchial responsiveness to methacholine. In the biopsies inflammatory cells, cytokine-producing cells, tenascin and laminin were visual zed by immunostaining. Patients with pSS had a higher number of neutrophils and mast cells than healthy controls, while the number of eosinophils was similar in the two groups. The number of IL-8-positive cells was higher in pSS butthe numbers of IL-4-and IL-5-positive cells were not significantly different between pSS and healthy controls. The numbers of T cells in patients with pSS were higher than in healthy controls, while the numbers of CD25-positive cells were similar to the healthy controls. The degree of epithelial integrity in patients with pSS was significantly lower than in the control group and the tenascin and laminin layers were significantly thicker in the pSS group. There was a correlation between the number of mast cells and the thickness of the tenascin and laminin layers in pSS. In conclusion, we found that the cellular pattern in the bronchial mucosa of patients with pSS displayed large numbers of neutrophils, mast cells and T-lymphocytes. These changes in inflammatory cell numbers seemed to relate to the observed increased epithelial damage and structural changes of the subepithelium. The structural findings, but not the pattern of inflammatory cells, are shared with atopic asthma and may relate to the increased bronchial hyper-responsiveness seen in both diseases.
11549844 Abnormal organogenesis in salivary gland development may initiate adult onset of autoimmun 2001 OBJECTIVES: Salivary gland organogenesis was evaluated in NOD mice, an animal model for autoimmune exocrinopathy, to determine when disease onset is first present in the target tissues. METHODS: Submandibular glands were removed for histological, immunohistochemical and biochemical evaluation from neonatal NOD and congenic strains as well as healthy control C57BL/6 mice. RESULTS: Histomorphological analyses of neonatal submandibular glands, the primary target for autoimmune exocrinopathy at 1 day postpartum, revealed delayed morphological differentiation during organogenesis in autoimmune-susceptible NOD mice when compared to nonsusceptible C57BL/6 mice. Acinar cell proliferation was reduced, while expression of Fas, FasL and bcl-2 were increased. Acinar cell proliferation was reduced, while expression, of Fas, FasL and bcl-2 were increased. Throughout the preweaning period (21 days) submandibular glands from NOD and NOD congenic strains aberrantly expressed an increased matrix metalloproteinase (MMP)-2 and MMP-9 activity. Substitution of two susceptibility alleles (Idd3 and Idd5) in NOD mice resulted in an hierarchical and additive reversal of delayed organogenesis, elevated MMP-9 activity, and aberrant expression of parotid secretory protein. DISCUSSION: NOD-derived mice whose submandibular glands showed normal organogenesis did not progress to develop autoimmune exocrinopathy. Altered organogenesis of target tissue may therefore provide a cellular microenvironment capable of activating autoimmunity.
11485925 Lymphocyte migration to inflamed lacrimal glands is mediated by vascular cell adhesion mol 2001 Aug Sjogren's syndrome is an autoimmune disease characterized by inflammation and destruction of lacrimal and salivary glands. The development of the inflammation requires the migration of lymphocytes from the blood into these tissues. This migration involves multistep cascades with binding of lacrimal gland endothelial adhesion molecules to their ligands on circulating lymphocytes. We used nonobese diabetic mice, which develop autoimmune-mediated lacrimal gland inflammation, as an experimental model to define the adhesion molecules that control lymphocyte migration into inflamed lacrimal glands. We found that vascular endothelia in inflamed areas of lacrimal gland expressed vascular cell adhesion molecule (VCAM)-1 and the peripheral node addressin (PNAd), but not mucosal addressin cell adhesion molecule-1. Most lymphocytes in the inflamed glands expressed alpha(4) integrin, L-selectin, and lymphocyte function-associated antigen (LFA)-1. In vivo studies revealed that antibodies against VCAM-1, alpha(4) integrin, PNAd, L-selectin, or LFA-1 almost completely blocked lymphocyte migration from blood into inflamed lacrimal glands. There was no inhibition of migration by antibodies against mucosal addressin cell adhesion molecule-1 or alpha(4)beta(7) integrin. These results indicate that endothelial/lymphocyte adhesion cascades involving VCAM-1/alpha(4)beta(1) integrin, PNAd/L-selectin, and LFA-1 control the migration of lymphocytes into inflamed lacrimal gland. These adhesion molecules offer potential therapeutic targets to block the development of lacrimal gland inflammation and destruction.
10725063 Antibodies to CD4 in primary Sjögren's syndrome. 2000 Feb OBJECTIVE: The purpose of this study was to examine whether antibodies against CD4 are present in patients with primary Sjögren's syndrome, and to explore the possible correlation between these antibodies and the CD4+ T lymphocyte depletion that is seen in some Sjögren patients. METHODS: Sera from 214 patients with primary Sjögren's syndrome, 154 healthy blood donors, 38 age- and sex-matched controls without autoimmune disease, and 77 HIV-1-seropositive individuals were analysed by an enzyme-linked immunosorbent assay (ELISA) using recombinant soluble CD4 as the antigen. RESULTS: Anti-CD4 antibodies were observed more frequently in patients with Sjögren's syndrome (12.6%) as compared with the control groups (0.6%) (P < 0.001), and at a level similar to that seen among the HIV-1 patients (13.0%). However, no correlation was found between the presence of anti-CD4 antibodies and CD4+ T lymphocytopenia in the Sjögren patients. CONCLUSION: This is the first study that shows anti-CD4 antibodies in patients with primary Sjögren's syndrome. The significance of these antibodies in the immunopathogenesis of Sjögren's syndrome remains to be determined.
10620394 Stimulation with carbachol alters endomembrane distribution and plasma membrane expression 1999 Dec The events that lead to Sjögren's autoimmune processes in the lacrimal gland remain poorly understood. The acinar cell's responses to acute cholinergic stimulation include release of secretory products across the apical plasma membrane (apm) and a number of processes related to traffic between endomembrane compartments and the basal-lateral plasma membranes (blm), such as recruitment of Na, K-ATPase, accelerated recycling, and accelerated transcytosis of secretory IgA. We tested the hypothesis that stimulation-induced acceleration of endomembrane traffic is accompanied by changes in compartmentation and increased blm expression of proteins that are normally sequestered in endomembrane compartments. Isolated rabbit lacrimal gland acinar cells were cultured in serum-free media for 2 days. After harvesting, cells were incubated with or without 10 microm carbachol at 37 degrees C for 20 min. Cells were lysed, and lysates were analysed by isopycnic centrifugation on sorbitol gradients. Galactosyltransferase catalytic activity was determined biochemically. Different forms of cathepsin B were detected by Western blotting. Carbachol stimulation decreased the contents of beta-hexosaminidase, alpha-glucosidase, and protein in secretory vesicles and increased them in specific compartments of the trans-Golgi network (ld-tgns). Stimulation also caused levels of galactosyltransferase, preprocathepsin B, and procathepsin B to increase two- to three-fold in the blm as well as increasing in the ld-tgns. Other changes caused by sustained stimulation included: (a) increased levels of protein and procathepsin B in compartments of the lysosomal pathway; (b) changes in the distributions of Rab5 within the endomembrane system; (c) changes in the distribution of Rab6 within the Golgi complex and tgn; (d) decreased expression of acid phosphatase and MHC class II molecules in the blm; and (e) decreased total content of Na,K-ATPase, which appeared to have been selectively depleted from the tgn and blmre. We propose that the normal compartmentation of certain proteins may allow them to remain cryptic, such that they are not subject to central tolerance. Stimulation-induced increases in the levels expressed at the blm or secreted to the interstitium may, therefore, contribute to initiation of local autoimmune responses.